Background Etiology and pathogenesis of juvenile idiopathic arthritis (JIA), which prevails among pediatric rheumatic diseases, are insufficiently clear. The study of molecular-genetic basis of JIA is of great interest for revealing genetic predisposition and early diagnosis.
Objectives The present study aimed to analyze seven SNPs in five genes involved in immune and inflammatory responses: TNFα (rs1800629, rs361525), PTPN22 (rs24766012), MIF (rs755622, rs5844572), CTLA4 (rs5742909), STAT4 (rs7574865), as well as in two DNA repair genes XPD (rs1799793) and XRCC1 (rs25487) in different conditions.
Methods 94 patients diagnosed with JIA (mean age 8.78±5.21), 95 children with articular syndrome (mean age7.90±4.81) and 164 hospital controls without any signs of autoimmune or inflammatory diseases (mean age13.99±2.68) were included in the study. The JIA patients were divided into subgroups according to IIAR classification criteria; among them 63 patients were diagnosed with oligoarthritis and 16 with RF- polyarthritis. Genomic DNA was extracted from blood samples by means of phenol-chloroform method. SNPs were genotyped using PCR-RFLP or fragmental analysis.
Results The allele frequencies for all SNPs in the hospital control group were similar to those characteristic of other Europeans. No differences were found between the frequencies of the TNFα risk alleles across all three groups. Hence, both SNPs in the TNFα locus were not associated with JIA and other articular pathologies in our study. The same is true for -318C>T CTLA4 polymorphism. Unlike these genes, PTPN22 C1858T polymorphism influenced developing arthritis in children since heterozygous CT genotype was associated with articular pathology (rather than JIA) in the total group (OR=1.87, 95% CI [1.06–3.30], p=0.04), especially in males (OR=3.50, 95% CI [1.61–7.63], p=0.0016). In the latter case, it was effective even being combined with any genotypes in the -308G>A TNFα locus (OR=2.73, 95% CI [1.19–6.24], p=0.018). When analyzing MIF polymorphisms (rs755622 and rs5844572), the evident trend to increased carrying genotypes containing the risk allele MIF-173C was observed in females with JIA as compared to controls and significantly elevated frequency of this risk allele in females with RF- polyarthritis as compared to males (p =0.037). In females with JIA, increased frequency of heterozygous MIF-794 CATT7,8 genotype as compared to the controls (OR =7.78, 95% CI [0.95 – 63.8], p=0,056) was also revealed. STAT4 polymorphism (rs7574865) demonstrated subtype-related association with JIA due to increased frequency of the minor allele in patients with polyarthitic form of JIA as compared to both hospital controls (p=0.01; OR =2.45; 95% CI [1.19–5.04]) and other articular pathology (p=0.001; OR =3.37; 95% CI [1.56–7.28]). The same SNP was also associated with developing arthritis in females. As to role of DNA repair genes, carriers of XPD heterozygous Asp/Asn genotype had an enhanced risk of JIA in females (OR=2.14; 95% CI [1.05–4.35]; p=0.05).
Conclusions Thus, the gender- and subtype-specific associations of some SNPs studied with developing joint pathologies including JIA are found in the Belarusian child population.
Disclosure of Interest None declared